The present invention relates to benzene derivatives useful for the treatment of various inflammatory diseases and pharmaceutical compositions containing them.
It is known that various inflammatory diseases, rheumatoid diseases, immunoreactive diseases, cancer metastasis and viral diseases are caused by the abnormal production of inflammatory cytokines and matrix metalloprotease and also by the increase in the expression of inflammatory cell adhesion molecules.
Although various medicines for these diseases were developed in the prior art, further development of a medicine having a stronger efficiency, higher safety and weaker side effects is demanded.
The pathophysiological states of various chronic inflammatory diseases are considered to be caused by the continuous production of inflammation mediators such as cytokines [particularly, inflammatory cytokines including IL-1, IL-2, IL-6, IL-8 and tumor necrotizing factor (TNF)], adhesion molecules, tissue destroying enzymes (such as matrix metalloprotease), etc. by the continuous extracellular stimulation.
The inflammatory mediators are produced because the gene expression is activated by the extracellular stimulation. A substance having the most important role in this step is a transcription factor known as AP-1 or NF-kappa B. Namely, it is expected that when the activation of AP-1/NF-kappa B can be inhibited, the development of inflammation and the advance thereof into chronic stage can be prevented and that such a method will be a hopeful treatment of inflammatory diseases such as rheumatoid arthritis and various autoimmune diseases (V. C. Foletta et al., [Journal of Leukocyte Biology, 63, 139-152, 1998], P. J. Barnes et al., [The new England Journal of Medicine, 336, 1066-1071, 1997] and M. J. Suto et al., [Current Pharmaceutical Design, 3, 515-528, 1997]).
Glucocorticoid hormone (GC) which strongly inhibits the activation of intracellular AP-1 and NF-kappa B has been used as a powerful anti-inflammatory agent and immunosuppressant. However, the use of GC as a medicine is limited because it has various side effects due to hormonic action thereof and it causes rebound phenomenon.
The object of the present invention is to provide benzene derivatives having a remarkable medicinal effect and only a slight side effect and useful for the treatment of chronic inflammatory diseases.
Another object of the present invention is to provide a pharmaceutical composition containing the benzene derivative.
The above-described and other objects of the present invention will be apparent from the following description and Examples.
After intensive investigations made for the purpose of finding compounds having a strong activity of inhibiting the activation of AP-1 and NF-kappa B and useful as a strong remedy for chronic inflammatory diseases, the inventors have found that compounds of general formula (I) which will be described below have this effect. The present invention has been completed on the basis of this finding.
Namely, the present invention relates to benzene derivatives of the following general formula (I) or pharmaceutically acceptable salts thereof: 
wherein
R1 represents a cycloalkyl group having a substituent or a cycloalkenyl group having a substituent, R2 represents hydrogen atom or an alkyl group, R3 to R10, which may be the same or different from each other, represent hydrogen atom, a halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, trifluoromethyl group, an alkyl group, an alkoxyl group, an alkylthio group, an amino group which may be substituted with an alkyl group or an amino-protecting group, an acyloxy group, an acyl group, carboxyl group, an alkoxycarbonyl group or carbamoyl group,
xe2x88x92Y represents a group of following general formula (II), (III) or (IV): 
wherein
R11 and R13 each represent hydrogen atom or an alkyl group, R12 and R14 each represent an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent, an aromatic heterocyclic group having one or more hetero atom, which may have a substituent, or a saturated heterocyclic group having one or more hetero atoms, which may have a substituent, and R15 and R16 each represent an alkyl group or an aryl group which may form a ring together, and n and m each represent an integer selected from among 0 to 6, and
xe2x80x94Xxe2x80x94 represents an interatomic bond, or any of xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHR17xe2x80x94, xe2x80x94Oxe2x80x94CHR18xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Sxe2x80x94CHR19xe2x80x94, xe2x80x94CHR20xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94NR21xe2x80x94, xe2x80x94NR22xe2x80x94SO2xe2x80x94, xe2x80x94NR23xe2x80x94, xe2x80x94NR24xe2x80x94CHR25xe2x80x94, xe2x80x94CHR26xe2x80x94NR27xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90NOR28)xe2x80x94, xe2x80x94C(xe2x95x90CHR29)xe2x80x94, xe2x80x94COxe2x80x94CHR30xe2x80x94, xe2x80x94CHR31xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR32xe2x80x94, xe2x80x94NR33xe2x80x94COxe2x80x94, xe2x80x94CR34R35xe2x80x94, xe2x80x94CHR36xe2x80x94CHR37xe2x80x94 and xe2x80x94CR38xe2x95x90CR39xe2x80x94 wherein R17, R18, R19, R20, R21, R22, R25, R26, R29, R30, R31, R32, R33, R34, R38 and R39 each represent hydrogen atom or an alkyl group, R23, R24, R27 and R28 each represent hydrogen atom, an alkyl group or an acyl group, R36 and R37 each represent hydrogen atom, hydroxyl group or an alkyl group, and R35 represents hydrogen atom, hydroxyl group, mercapto group, cyano group, an alkyl group, which may have a substituent, an alkoxyl group, an alkylthio group, an acyloxy group, an amino group which may be substituted with an alkyl group or an amino-protecting group, carboxyl group, an alkoxycarbonyl group or carbamoyl group.
The present invention provides a pharmaceutical composition, particularly AP-1 and NF-kappa B activation inhibitor, inflammatory cytokine production inhibitor, matrix metalloprotease production inhibitor and inflammatory cell adhesion molecule expression inhibitor. They can be used as anti-inflammatory agent, antirheumatic agent, immunosuppressant, cancerous metastasis inhibitor, remedy for arteriosclerosis and antiviral agent, which contains the above-described benzene derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The detailed description of the present invention will be made below.
The term xe2x80x9chalogen atomsxe2x80x9d include fluorine atom, chlorine atom, bromine atom and iodine atom.
The term xe2x80x9chetero atomsxe2x80x9d herein indicates oxygen atom, sulfur atom and nitrogen atom. Among them, nitrogen atom is preferred.
The term xe2x80x9ccycloalkyl groupsxe2x80x9d herein indicates cyclic alkyl groups of 3 to 6 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. Among them, cyclopropyl group is preferred.
The term xe2x80x9ccycloalkenyl groupsxe2x80x9d herein indicates cyclic alkenyl groups having 3 to 6 carbon atoms such as cyclopropenyl group, cyclobutenyl group, cyclopentenyl group and cyclohexenyl group.
The term xe2x80x9calkyl groupsxe2x80x9d herein indicates linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, tert-pentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group and 2-hexyl group. Among them, methyl group and ethyl group are preferred.
The term xe2x80x9calkoxyl groupsxe2x80x9d herein indicates linear or branched alkoxyl groups having 1 to 6 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy group. Among them, methoxy group and ethoxy group are preferred.
The term xe2x80x9calkylthio groupsxe2x80x9d indicates linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, sec-butylthio group and tert-butylthio group.
The term xe2x80x9camino groups which may be substituted with an alkyl groupxe2x80x9d indicates unsubstituted amino groups or amino groups mono- or di-substituted with alkyl group(s). The alkyl groups are those listed above as examples of the xe2x80x9calkyl groupsxe2x80x9d. xe2x80x9cAmino groups which may be substituted with an alkyl groupxe2x80x9d are, for example, amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group and methylethylamino group.
Amino-protecting groups are ordinary protecting groups which are not particularly limited so far as they are capable of protecting the amino group from reactions. They include, for example, acyl groups such as formyl group, acetyl group and pivaloyl group; and alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group and fluorenyl-9-methoxycarbonyl group.
The term xe2x80x9cacyloxy groupsxe2x80x9d indicates linear or branched acyloxy groups having 1 to 6 carbon atoms or acyloxy groups having a substituted or unsubstituted aryl group, such as formyloxy group, acetyloxy group, propionyloxy group, butyroyloxy group, isobutyroyloxy group, valeroyloxy group, isovaleroyloxy group, pivaloyloxy group, hexanoyloxy group, acryloyloxy group, methacryloyloxy group, crotonoyloxy group, isocrotonoyloxy group, benzoyloxy group and naphthoyloxy group.
The term xe2x80x9cacyl groupsxe2x80x9d indicates linear or branched acyl groups having 1 to 6 carbon atoms or acyl groups having a substituted or unsubstituted aryl group, such as formyl group, acetyl group, propionyl group, butyroyl group, isobutyroyl group, valeroyl group, isovaleroyl group, pivaloyl group, hexanoyl group, acryloyl group, methacryloyl group, crotonoyl group, isocrotonoyl group, benzoyl group and naphthoyl group.
The term xe2x80x9calkoxycarbonyl groupsxe2x80x9d indicates those having a linear or branched alkyl group 1 to 6 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group and tert-butoxycarbonyl group.
The term xe2x80x9ccarbamoyl groupsxe2x80x9d herein indicates, for example, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, pyrrolidinocarbonyl group and piperidinocarbonyl group.
The term xe2x80x9caryl groupsxe2x80x9d herein indicates, for example, phenyl group, pentenyl group, indenyl group, naphthyl group and fluorenyl group. Among them, phenyl group is preferred.
The term xe2x80x9caromatic heterocyclic groups having one or more hetero atomsxe2x80x9d herein indicates, for example, pyranyl group, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, pyrazolyl group, furazanyl group, thiadiazolyl group and indolyl group. Among them, pyridyl group, pyrimidyl group, imidazolyl group and triazolyl group are preferred. Pyridyl group is particularly preferred.
The term xe2x80x9csaturated heterocyclic groups having one or more hetero atomsxe2x80x9d herein indicates, for example, pyrrolidyl group, piperidyl group, piperazinyl group, morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group and tetrahydrothienyl group. 2-Pyrrolidyl group is particularly preferred.
The term xe2x80x9chaving a substituentxe2x80x9d in the expressions xe2x80x9ccycloalkyl groups having a substituentxe2x80x9d, xe2x80x9ccycloalkenyl groups having a substituentxe2x80x9d and xe2x80x9ccyclopropyl group having a substituentxe2x80x9d indicates that such groups are substituted with at least one substituent. The substituents may be the same or different from one another, and the position of the substituent is not particularly limited. Concretely, the substituents are, for example, halogen atoms, alkyl groups which may have a substituent, carboxyl group, alkoxycarbonyl groups, cyano group and amino group which may be substituted with an alkyl group or amino-protecting group.
The term xe2x80x9cwhich may have a substituentxe2x80x9d in the expressions xe2x80x9calkyl groups which may have a substituentxe2x80x9d, xe2x80x9ccycloalkyl groups which may have a substituentxe2x80x9d and xe2x80x9ccycloalkenyl groups which may have a substituentxe2x80x9d indicates that these groups may have a substituent or substituents on the alkyl chain or on the ring. The substituents may be the same or different from each other and the position of the substituent is not particularly limited. The substituents are, for example, halogen atoms, alkyl groups which may have a substituent, hydroxyl group, alkoxyl groups, carboxyl group, alkoxycarbonyl groups, cyano group and amino group which may be substituted with an alkyl group or an amino-protecting group.
The term xe2x80x9cwhich may have a substituentxe2x80x9d in the expressions xe2x80x9caryl groups which may have a substituentxe2x80x9d and xe2x80x9caromatic heterocyclic groups having one or more hetero atoms, which may have a substituentxe2x80x9d indicates that these groups may have 1 to 3 substituents on the ring. The substituents may be the same or different from each other and the position of the substituent is not particularly limited. The substituents are, for example, halogen atoms, alkyl groups which may have a substituent, hydroxyl group, alkoxyl groups, carboxyl group, alkoxycarbonyl groups, cyano group and amino groups which may be substituted with an alkyl group or an amino-protecting group.
The term xe2x80x9cwhich may have a substituentxe2x80x9d in the expression xe2x80x9csaturated heterocyclic rings having one or more hetero atoms, which may have a substituentxe2x80x9d indicates that these groups may have 1 to 10 substituents on the ring. The substituents may be the same or different from each other and the position of the substituent is not particularly limited. The substituents are, for example, halogen atoms, alkyl groups which may have a substituent, hydroxyl group, alkoxyl groups, carboxyl group, alkoxycarbonyl groups, cyano group and amino groups which may be substituted with an alkyl group or an amino-protecting group.
The expression of R15 and R18 reading xe2x80x9can alkyl group or aryl group which may form a ring togetherxe2x80x9d indicates groups of, for example, following formulae (V), (VI) and (VII) when they form a ring: (VII) 
In the benzene derivatives of the present invention, those shown by general formula (I) wherein R1 represents a cycloalkyl group having a substituent and pharmaceutically acceptable salts thereof exhibit a remarkable effect. The substituents are preferably alkyl groups, more preferably lower alkyl groups having 1 to 3 carbon atoms. Particularly preferred substituents are di-lower alkyl groups and particularly dimethyl group. A remarkable effect of the compounds is obtained when R1 is a cyclopropyl group having the above-described substituent, particularly 2,2-dimethylcyclopropyl group or 2,2-dichlorocyclopropyl group.
R2 is preferably hydrogen atom.
R3 to R10 are each preferably hydrogen atom, a lower alkyl group or a halogen. They are each particularly preferably hydrogen atom.
Y is preferably a group of general formula (II).
R11 and R13 are each preferably hydrogen atom.
R12 and R14 are each preferably a cycloalkyl group having a substituent. The substituent is preferably an alkyl group, particularly an alkyl group having 1 to 3 carbon atoms, or a di-lower alkyl group, particularly dimethyl group. R12 and R14 are each more preferably a cyclopropyl group having the above-described substituent, particularly 2,2-dimethylcyclopropyl group or 2,2-dichlorocyclopropyl group.
R15 and R16 are each an alkyl or aryl group which may form a ring together, preferably a group of formula (V), (VI) or (VII) given above.
X is preferably xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHR17xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Sxe2x80x94CHR19xe2x80x94, xe2x80x94SO2xe2x80x94NR21xe2x80x94, xe2x80x94NR23xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90NOR28)xe2x80x94, xe2x80x94C(xe2x95x90CHR29)xe2x80x94, xe2x80x94COxe2x80x94NR32xe2x80x94, xe2x80x94CR34R35xe2x80x94, xe2x80x94CHR36xe2x80x94CHR37xe2x80x94 or xe2x80x94CR38xe2x95x90CR39xe2x80x94 wherein R17, R19, R23, R28, R29, R34, R36 and R37 are each preferably hydrogen atom. R21 and R32 are each preferably hydrogen atom or a lower alkyl group. R35 is preferably hydrogen atom, hydroxyl group, an alkyl group, which may have a substituent, an alkoxyl group, an acyloxy group, an amino group which may be substituted with an amino-protecting group or an alkoxycarbonyl group.
X is further preferably xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CHR19xe2x80x94, xe2x80x94NR23xe2x80x94, xe2x80x94CR34R35xe2x80x94 or xe2x80x94CHR36xe2x80x94CHR37xe2x80x94. X is particularly preferably xe2x80x94CR34R35xe2x80x94. R19, R23, R34, R35, R36 and R37 are each preferably as described above.
When R1 in general formula (I) is cyclopropyl group having a substituent, it is preferred that the carbon atom adjacent to carbonyl group on cyclopropyl group has absolute configuration S. On the other hand, when R1 in general formula (I) is cyclopropyl group having a substituent, it is also preferred that the carbon atom adjacent to carbonyl group on cyclopropyl group has absolute configuration R.
A remarkable effect can be obtained when both R1 and R12, in general formula (I), are 2,2-dimethylcyclopropyl group or 2,2-dichlorocyclopropyl group and n is 0, or when both R1 is 2,2-dimethylcyclopropyl group or 2,2-dichlorocyclopropyl group, R12 is an aryl group which may have a substituent and n is 1.
Benzene derivatives of following general formula (Ia) or pharmaceutically acceptable salts thereof are preferred in the compounds of general formula (I): 
wherein
R1 and R2 are as defined in general formula (I),
Y1 is as defined in general formulae (II) and (III),
R11, R13, n and m are as defined in general formulae (II) and (III),
R12 and R14 each represent an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent or an aromatic heterocyclic group having one or more hetero atoms, which may have a substituent, and
xe2x80x94X1xe2x80x94 represents xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHR17xe2x80x94, xe2x80x94CHR18xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Sxe2x80x94CHR19xe2x80x94, xe2x80x94CHR20xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CSxe2x80x94, xe2x80x94CSxe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94NR21xe2x80x94, xe2x80x94NR22xe2x80x94S2xe2x80x94, xe2x80x94NR23xe2x80x94, xe2x80x94NR24xe2x80x94CHR25xe2x80x94, xe2x80x94CHR26xe2x80x94NR27xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90NOR28)xe2x80x94, xe2x80x94C(xe2x95x90CHR29)xe2x80x94, xe2x80x94COxe2x80x94CHR30xe2x80x94, xe2x80x94CHR31xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR32xe2x80x94, xe2x80x94NR33xe2x80x94COxe2x80x94, xe2x80x94CR34R35xe2x80x94, xe2x80x94CHR36xe2x80x94CHR37xe2x80x94 or xe2x80x94CR38xe2x95x90CR39xe2x80x94 wherein R17 through R39 are as defined in formula (I).
Preferred examples of R1, R2, R11, R13, n, m, R12, R14 and R17 through R39 in general formula (Ia) are as described above with reference to formula (I).
The pharmaceutically acceptable salts are as follows: When the compounds of the present invention are completely acidic, the salts of them are, for example, ammonium salts, alkali metal salts (such as, preferably, sodium and potassium salts), alkaline earth metal salts (such as, preferably calcium and magnesium salts) and organic base salts such as dicyclohexylamine salts, benzathine salts, N-methyl-D-glucan salts, hydramine salts, and salts of amino acids such as arginine and lysine. When the compounds of the present invention are completely alkaline, the salts of them are, for example, acid-addition salts such as those with inorganic acids, for example, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and also those with organic acids, for example, acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid and monomethylsulfuric acid. If necessary, the salts may be in a hydrous form of in the form of hydrates.
The compounds of the present invention may be in the form of isomers such as optical isomers and geometrical isomers, hydrates, solvated products and crystals of any form.
The compounds of the present invention can be synthesized by methods described below.
For example, compounds of the present invention represented by above general formula (I), wherein xe2x80x94Y is represented by formula (II), n is 0 and both ends of which are the same, can be obtained by reacting one equivalent of a corresponding diamine compound with at least two equivalents of a corresponding acid halide such as, e.g. an acid chloride, in the presence of a base or by reacting it with at least two equivalents of a carboxylic acid in the presence of a coupling reagent as shown below: 
wherein X is as defined above, R represents hydrogen atom or an alkyl group, Rxe2x80x2 represents a cycloalkyl group having a substituent or a cycloalkenyl group having a substituent, and Z represents a halogen atom.
The compound wherein xe2x80x94Xxe2x80x94 is xe2x80x94COxe2x80x94, obtained by the above-described reaction, can be converted into compounds of the following formulae of the present invention by, for example, a method shown in Examples given below. 
wherein Rxe2x80x2 represents a cycloalkyl group having a substituent or a cycloalkenyl group having a substituent.
Compounds of the present invention represented by above general formula (I), wherein xe2x80x94Y is represented by formula (II) and both ends of which are different from each other, can be obtained by reacting one equivalent of a corresponding diamine compound with about one equivalent of a corresponding acid halide such as, e.g. an acid chloride, in the presence of a base or by reacting one equivalent of the diamine compound with about one equivalent of a carboxylic acid in the presence of a coupling reagent to introduce a substituent into an end of the diamine compound and then reacting the obtained product with an acid halide or carboxylic acid having a structure different from the acid halide or carboxylic acid used in the previous step as shown below: 
wherein X is as defined above, R represents hydrogen atom or an alkyl group, Rxe2x80x2 represents a cycloalkyl group having a substituent or a cycloalkenyl group having a substituent, Rxe2x80x3 represents an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent, an aromatic heterocyclic group having one or more hetero atoms, which may have a substituent, or a saturated heterocyclic ring having one or more hetero atoms, which may have a substituent, and Z represents a halogen atom.
Further, compounds of the above formula wherein xe2x80x94Xxe2x80x94 represents xe2x80x94COxe2x80x94, obtained by the above-described reaction, can be converted into compounds shown in Examples given below by the above-described functional group-converting reaction.
Intended compounds of above formula (I) wherein xe2x80x94Y is represented by formula (III) in the present invention can be obtained by reacting one equivalent of a corresponding diamine compound as the starting material with about one equivalent of a corresponding acid halide such as an acid chloride in the presence of a base, or by reacting one equivalent of a diamine compound with about one equivalent of a carboxylic acid in the presence of a coupling reagent to introduce a substituent into an end of the diamine compound and then reacting the obtained product with an alkyl halide which may have a substituent or with an aldehyde which may have a substituent in the presence of a reducing agent. 
wherein X is as defined above, R represents hydrogen atom or an alkyl group, Rxe2x80x2 represents a cycloalkyl group having a substituent or a cycloalkenyl group having a substituent, Rxe2x80x3 represents an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent, an aromatic heterocyclic group having one or more hetero atoms, which may have a substituent, or a saturated heterocyclic group having one or more hetero atoms, which may have a substituent, and Z and W each represent a halogen atom.
The compounds of the present invention can be synthesized by applying these processes or by an ordinary process.
The compounds of the present invention obtained by the above-described processes can be purified by a purification method usually employed in the synthesis of organic compounds such as extraction, distillation, crystallization or column chromatography.
The compounds of the present invention thus obtained have an activity of inhibiting the activation of AP-1 and NF-kappa B, and they are useful for the treatment of inflammatory diseases caused by these transcription factors. Namely, these compounds inhibit gene expression of inflammatory cytokines, matrix metalloprotease and inflammatory cell adhesion molecules. They are useful as anti-inflammatory agent, antirheumatic agent, immunosuppressant, cancerous metastasis inhibitor and antiviral agent without side effects such as hormonal effects.
When the compounds of the present invention are used as anti-inflammatory agents, they can given by oral, intravenous or percutaneous administration or by eye dropping method. The dosage, which varies depending on the symptoms and age of the patient and also administration method, is usually 1 to 3,000 mg/kg/day.
Preparations containing the compounds of the present invention can be prepared by an ordinary method. The preparations may be in the form of an injection, tablets, granules, grains, powders, capsules, cream or suppositories. Carriers used for producing the preparations are, for example, lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, calcium salt of carboxymethylcellulose, magnesium stearate, talc, acetylcellulose, sucrose, titanium oxide, benzoic acid, para-hydroxybenzoic esters, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactants, simple syrup, citric acid, distilled water, ethanol, glycerol, propylene glycol, macrogol, sodium monohydrogenphosphate, sodium dihydrogenphosphate, sodium phosphate, glucose, sodium chloride, phenol, thimerosal, p-hydroxybenzoic esters and sodium hydrogensulfite. They are suitably selected depending on the form of the preparation, and mixed with the compounds of the present invention.
The amount of the active ingredient of the present invention in the preparation of the present invention is not particularly limited because it varies in a wide range depending on the form of the preparation. However, the amount is usually 0.01 to 100% by weight, and preferably 1 to 100% by weight, based on the whole composition.